TWI354670B - (s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-met - Google Patents
(s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-met Download PDFInfo
- Publication number
- TWI354670B TWI354670B TW094141939A TW94141939A TWI354670B TW I354670 B TWI354670 B TW I354670B TW 094141939 A TW094141939 A TW 094141939A TW 94141939 A TW94141939 A TW 94141939A TW I354670 B TWI354670 B TW I354670B
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- Prior art keywords
- dihydrate
- hydrochloride
- sulfonyl
- methyl
- strength
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
Description
1354670 九、發明說明: 【發明所屬之技術領域】 本發明係有關於吸濕安定性優良之(3)_(_)_1_(4_氟基異喹 啉-5-基)續醯基-2-甲基-1,4-升哌畊鹽酸鹽•二水合物。 【先前技術】 (8)-(-)-1-(4-氟基異啥琳-5-基)續酿基_2_曱基_14_升略畊 鹽酸鹽係下式(1)表示之化合物(參照專利文獻1): [化1]1354670 IX. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention relates to (3) _(_)_1_(4_fluoroisoquinolin-5-yl) fluorenyl-2 which is excellent in hygroscopic stability. - Methyl-1,4-litre piped hydrochloride•dihydrate. [Prior Art] (8)-(-)-1-(4-Fluoroisoindol-5-yl) Continued Brewing Base_2_曱基_14_升略耕盐盐 The following formula (1) Compound represented (refer to Patent Document 1): [Chemical 1]
•HC1 (1) 其為水溶性的無水結晶。另外,已知化合物⑴係腦梗 塞、腦出血、物蛛膜下出血、腦浮腫等的腦血管障礙之預 防及治療劑,特別是其能用作為腦中風等的腦血管痙攣疾 病的抑制劑(参照專利文獻1)。 :化合物⑴的結晶體僅知有⑻朴丨♦氣㈣ # t基)伽基·2-甲基-1,4.升Μ鹽酸㈣無水結晶… 「f水結晶」)(参照專利文獻”。該無水結晶的 水刀3 1 (卡氏法(K d Fis h 、 以%表示)以r)旬為1重量%(以下簡單地 但是’該無水結晶在25。 下,水分含量會隨著時間增加,:對濕度(RH)的條件 5)。另外,該無水結晶保存於相加至 下,則會發生吸濕現象,無水結晶的==的條件 的1晶構造產生變化而 J06868-971127.doc 伴隨產生體積變化。亦即,該無水結晶因吸濕現象而變化 結晶狀態。 一般而言,已知主藥或賦形劑顯示持有吸濕性等的問題 時,則會產生重量變化、結晶形變化、或因該等引起的體 積變化,而成為錠劑之硬度變化及裂開的原因。此種變化 每成製造錠劑上的不便。因&,製劑化步驟或製劑的保存 中需要使用無預吸濕性等問題的化合物。此外,伴隨有 吸濕之結晶形變化不僅成為原體本身之安定性或生物可用 性降低之主要原因,特別是作為高純度之醫藥品原體,此 種問題必需先解決。 因為即使疋化合物(1)之無水結晶亦伴隨有吸濕問題, 因此,必要有保存嚴密的濕度管理,但是,實際上非常困 難,因此需要有吸濕性低且保存安定性優良之上記醫藥品 原體。 [專利文獻1]國際公開第99/20620號手冊 【發明内容】 因此,本發明目的係改善因(S)-(-)-l-(4-氟基異喹啉-5-基)¾酿基-2-甲基一丨,4_升哌井鹽酸鹽無水結晶所具有之 吸濕ί·生而引起醫藥品原體之重量變化、結晶形變化或伴隨 S玄等的體積變化等的化學不安定性。 本發明者等’馨於上述事態,努力研究結果發現以下式 (2)表不之新賴氟基異喹啉_^基)磺醯基·2·甲 ,升底井鹽酸鹽•二水合物(以下亦簡稱「二水合 物」或「二水合物結晶」): 106868-971127.doc ♦HCl · 2Hj〇 (2) 合其吸濕安定性良好且為實質上非吸濕性的結晶,因而不 戶日有因吸濕而帶來的重量變化及結晶形變化,或伴隨該等 ^產生的體積變化,且熱安定性亦良好,而得以完成本發 供亦即,本發明係提供新穎氟基異喹啉_5·基) 只醯基-2-甲基-i,4-升哌畊鹽酸鹽•二水合物者。 另外,本發明係提供(S)-(-)-i_(4-氟基異喹琳_5_基)磺醯 基甲基-1,4-升哌啡鹽酸鹽•二水合物的製造方法其 特徵為將(S)-(-)-1 -(4-氟基異喹啉_5_基)磺醯基_2·甲基_ 1,4_ 升哌畊鹽酸鹽溶解於50〜10(TC的水,再添加親水性有機溶 劑’並冷却至〇〜3(TC。 再者本發明係k供含有(s)-(-)-1 _(4_說基異啥琳-5-基) 磺醯基-2-甲基_1,4_升哌畊鹽酸鹽•二水合物及藥學上可 容許之載體的醫藥組合物。 [發明的效果] 由於本發明之新穎氟基異喹啉_5•基)磺醯基· 2_甲基-1,4-升哌畊鹽酸鹽•二水合物係非吸濕性,因此可 避免因吸濕所帶來之各種問題,且對熱的安定性亦佳。因 此,本發明二水合物係保存及製劑製造上極有用之醫藥品 原體。 I06868-971127.doc 1354670 【實施方式】 本發明之新穎(S)-(-)-l-(4 基-1,4-升哌p井鹽酸鹽.二 造。 首先,0)-(-)4-(4-氟基異喹 升哌11井鹽酸鹽(1)可依如同下 一 土 ~醯基甲基_1’4- 方法製造: 工所示之專利文獻1上記載的• HC1 (1) It is a water-soluble anhydrous crystal. Further, the compound (1) is known to be a prophylactic and therapeutic agent for cerebrovascular diseases such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and brain edema, and particularly, it can be used as an inhibitor of cerebral vasospasm diseases such as stroke ( Refer to Patent Document 1). The crystal of the compound (1) is known only for (8) Park 丨 qi (4) # t ) 伽 · 2-methyl-1, 4. Μ Μ hydrochloric acid (4) anhydrous crystals... "f water crystal" (refer to the patent literature). Water-free crystal water jet 3 1 (Kard's method (K d Fis h, expressed in %) is 1% by weight in r) (hereinafter simply but 'the anhydrous crystal is at 25. The moisture content will increase with time :: Conditions for humidity (RH) 5). In addition, when the anhydrous crystals are stored and added to the bottom, moisture absorption occurs, and the 1-crystal structure of the condition of anhydrous crystal == changes. J06868-971127.doc The change in volume is accompanied by a change in the crystal state. In other words, it is known that the main drug or the excipient exhibits a change in weight and crystallization when it shows a problem of hygroscopicity or the like. The shape change, or the volume change caused by the above, becomes the cause of the hardness change and cracking of the tablet. This change is inconvenient in the manufacture of the tablet. Because of the &, the formulation step or the preservation of the preparation is required Use a compound that has no problems such as pre-hygroscopicity. In addition, it is accompanied by moisture absorption. The crystal form change is not only the main reason for the stability of the original body itself but also the decrease in bioavailability, especially as a high-purity pharmaceutical substance. This problem must be solved first, because even the anhydrous crystal of the hydrazine compound (1) is accompanied by absorption. Because of the wetness problem, it is necessary to have a strict humidity management, but it is actually very difficult. Therefore, it is necessary to have a low hygroscopicity and excellent preservation stability. [Patent Document 1] International Publication No. 99/20620 No. Manual [Summary of the Invention] Accordingly, the object of the present invention is to improve (S)-(-)-l-(4-fluoroisoquinolin-5-yl)3⁄4-bromo-2-methyl-anthracene, 4_ The chemical instability of the pharmaceutically acceptable pharmaceutically acceptable substance, the change in the crystal form, or the chemical change accompanying the volume change of S-Xuan et al. In the case of the situation, it was found that the following formula (2) shows the novel lysylfluoroiso-isoquinoline, sulfonyl-2, A, and the dihydrochloride hydrochloride dihydrate (hereinafter also referred to as "dihydrate" Or "dihydrate crystal"): 106868-971127. Doc ♦ HCl · 2Hj〇(2) It is a crystallization with good moisture absorption stability and is substantially non-hygroscopic, so there is no change in weight and crystal shape due to moisture absorption, or accompanying such ^ The resulting volume change, and the thermal stability is also good, and the present invention is completed, that is, the present invention provides a novel fluoroiso-isoquinoline _5·yl) fluorenyl-2-methyl-i,4-升 Pipeline hydrochloride•Dihydrate. Further, the present invention provides the production of (S)-(-)-i_(4-fluoroisohexylin-5-yl)sulfonylmethyl-1,4-liter piperidine hydrochloride•dihydrate. The method is characterized in that (S)-(-)-1 -(4-fluoroisoisoquinolin-5-yl)sulfonyl-2-methyl- 1,1_liter piperidine hydrochloride is dissolved in 50~ 10 (TC water, then add hydrophilic organic solvent' and cool to 〇~3 (TC. Further, the present invention is k for containing (s)-(-)-1 _(4_说基异啥琳-5 a pharmaceutical composition of a sulfonyl-2-methyl-1, 4-liter piperidine hydrochloride dihydrate and a pharmaceutically acceptable carrier. [Effect of the Invention] The novel fluorine group of the present invention Isoquinoline _5•yl)sulfonyl·2-methyl-1,4-litre piperidine hydrochloride•Dihydrate is non-hygroscopic, thus avoiding various problems caused by moisture absorption. Moreover, the stability to heat is also good. Therefore, the dihydrate of the present invention is a drug precursor which is extremely useful for preservation and preparation of a preparation. I06868-971127.doc 1354670 [Embodiment] The novel (S)-(- )-l-(4 base-1,4-liter piper p-hydrochloride. Manufactured. First, 0)-(-)4-(4-fluoroiso-isoquinoline 11 well hydrochloride (1) It can be manufactured as in the next soil-mercaptomethyl-1'4-method: as described in Patent Document 1
、氟基異喹啉_5_基)磺醯基_2_曱 艮合物(2)可藉由以下方法製 [化3], fluoroisoquinoline _5_ yl) sulfonyl 2 曱 艮 ( (2) can be produced by the following method [Chemical 3]
第三步瞭 [式中L1表4¾離基] :即,(SH+)-2-胺基丙醇和化合物(3)表示之磺酸衍生物 二乙胺存在下,藉由在二氯甲烷中反應而合成 W(第i步驟),接著,化合物(4)在三乙胺存在下,在:氣 曱院中和甲續酿氯反應,將經基曱續酿化H,和3_胺 基丙醇反應而合成化合物(5)(第2步驟),接著,化合物 置於四氫料中使用三苯基膦、偶氮f酸二異丙醋藉光延 106868-97] 127.doc ^54670 反應而閉環,藉此合成化合物 ⑷在乙醇中,請·氣化氣㈣丄步:),所得化合物 r4 A s ^ ^ 夜以鹽酸鹽製出(s)-(-)-i- (_鼠基異喹啉-5-基)磺醯基 〇)。 土 -1’4~升哌哨鹽酸鹽 將以上述方法所製造之⑻·(·)_ 磺酿基·2·甲基],4•升㈣鹽酸 ▲異喧琳基) 佳A 80V、沾ρ尖 现()冷解於5〇t〜loot (較 佳為80C)的水中,接著,一 水性有機溶劑,將藉由冷却至〇〜^在而^度―面添加親 0〜3(TC乾燥20〜3〇小時而可製 丨之結晶經由在 1 Γ4 ϋ A s ^ . 侍成為、·。晶之本發明(s)-(-)- (氟基異喹啉-5-基)磺醯基_2_甲 二水合物⑺。 甲基-Μ-升哌,鹽酸鹽· 水分含量相對於(s)-(-)_M4 £ | 甲其 氟基異喹啉-5-基)磺醯基-2- :基升則鹽酸鹽⑴’宜使用1〇〜2.〇倍重量,較佳 加IT.?重量。另外’親水性有機溶劑的量相對於所添 ,7 ,且使用2〜6倍量,較佳為用4倍量。 至:親水性有機溶劑,可列舉者有甲醇、乙醇、正丙 二、異丙醇、正丁醇等的醇類、丙嗣、n,n_二甲基尹酿 —甲亞石風、二乙二醇二W等’特別佳為乙醇、異丙 :丙酮彳却温度及乾燥溫度各為❹〜坑,較佳為室温 左右’乾燥時間為2〇〜3G小時,較佳㈣小時左右。 如此所付之本發明二水合物係、含有8⑽〜9侧之水分者 =氏法),較佳為含有8·87〜9 13%之水分者(卡氏法胸及 。此外’如圖7所示,在价、相對濕度92刪條件 下,在Μ日的經時變化中,本發明二水合物水分含量未變 106868-971127.doc 1354670 化,而判定為安定者。此外,本發明二水合物即使保存在 8〇°C、2星期之嚴苛條件下也不會產生分解等的問題亦 可判定熱安定性高者(表6)。The third step [in the formula, L1 table 43⁄4 leaving the base]: that is, (SH+)-2-aminopropanol and the compound (3) represented by the sulfonic acid derivative diethylamine, by reacting in dichloromethane And synthesizing W (i-th step), then, in the presence of triethylamine, in the presence of triethylamine, in the gas broth and the continuous chlorine-recombination reaction, the base is continuously brewed H, and 3-aminopropyl The compound (5) is synthesized by an alcohol reaction (second step), and then the compound is placed in a tetrahydrogen material using triphenylphosphine, azo-f-acid diisopropyl vinegar by light extension 106868-97] 127.doc ^54670 reaction Closed loop, thereby synthesizing compound (4) in ethanol, please gasification gas (4) step:), the obtained compound r4 A s ^ ^ night to produce (s)-(-)-i- Isoquinolin-5-yl)sulfonylhydrazine). Earth-1'4~ liter phenoxy hydrochloride will be made by the above method (8)·(·)_ sulfonyl 2·methyl], 4 • liter (tetra) hydrochloric acid ▲ isophthalene) A 80V, Dip 尖 尖 () cold solution in 5 〇 t ~ loot (preferably 80 C) in water, then, an aqueous organic solvent, will be cooled by 〇 ~ ^ in the ^ degree - face added pro 0 ~ 3 ( The TC is dried for 20 to 3 hours, and the crystals of the ruthenium can be formed by the method of (s)-(-)-(fluoroisoquinolin-5-yl) according to 1 Γ4 ϋ A s ^. Sulfonyl-2-methyldihydrate (7). Methyl-hydrazine-liter piperazine, hydrochloride · Moisture content relative to (s)-(-)_M4 £ | methyl fluoroisoquinolin-5-yl) The sulfonyl-2-:yl liter hydrochloride (1)' should preferably be used in an amount of from 1 to 2. by weight, preferably by weight. Further, the amount of the hydrophilic organic solvent is 4 to 6 times the amount of the hydrophilic organic solvent, and is preferably 4 times the amount. To: a hydrophilic organic solvent, which may be an alcohol such as methanol, ethanol, n-propane diacetic acid, isopropanol or n-butanol, or an anthracene, n, n-dimethyl ketone-a jasmine wind, two Ethylene glycol, W, etc., particularly preferably ethanol, isopropyl: acetone oxime, but the temperature and drying temperature are each ❹~pit, preferably about room temperature. The drying time is 2 〇 to 3 G hours, preferably about (4) hours. The dihydrate system of the present invention, which contains the water of 8 (10) to 9 on the side of the method, preferably contains 8·87 to 9 13% of water (Card's method and chest. In addition, 'Figure 7 As shown, under the conditions of valence and relative humidity 92, the moisture content of the dihydrate of the present invention did not change 106868-971127.doc 1354670 in the change over time of the next day, and was determined to be stable. In addition, the present invention The hydrate does not cause decomposition or the like even under the severe conditions of 8 ° C for 2 weeks, and the heat stability is also high (Table 6).
另一方面’(S)-( 1)-1-(4-氟基異喹啉-5-基)磺醯基·2·甲 基· Μ-升哌畊鹽酸鹽的無水結晶在相同條件下顯示隨著時 間水分含量增加,7曰後顯示高達40%之水分含量(圖6) ^ 本發明之二水合物作為基於腦血管障礙之疾病的預防或 治療劑甚有用,該腦血管障礙為腦梗塞、腦出血、蜘蛛膜 下出血、腦浮腫等。本發明二水合物的投與形態並未特別 限疋,經口投與或非經口投與(肌肉内、皮下、静脈内、 栓劑、眼藥等)之任一者均可。 調製經口用製劑時,在添加賦形劑、依需要之結合劑、 崩散劑、潤滑劑、t色劑、矯味矯臭劑等的藥學上可容許 之載體後’依节法可做成為鍵劑、被覆鍵劑、顆粒劑、膠On the other hand, the anhydrous crystallization of '(S)-(1)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-hydrazine-literic acid hydrochloride under the same conditions The following shows an increase in moisture content over time, showing up to 40% moisture content after 7曰 (Fig. 6) ^ The dihydrate of the present invention is useful as a prophylactic or therapeutic agent for diseases based on cerebrovascular disorders, which is Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, brain edema, etc. The administration form of the dihydrate of the present invention is not particularly limited, and any of oral administration or non-oral administration (intramuscular, subcutaneous, intravenous, suppository, ophthalmic, etc.) may be employed. When preparing a preparation for oral administration, after adding a pharmaceutically acceptable carrier such as an excipient, a binding agent, a disintegrating agent, a lubricant, a t-coloring agent, a flavoring agent, etc., it can be used as a bonding agent. , coated with key agent, granules, glue
囊齊丨冷液劑、糖漿劑、酏劑、油性或水溶性的懸濁液劑 等。 賦形劑可列舉者有例如乳糖、玉米粉、白糖、葡萄糖、 山梨糖醇、結晶纖維素等。結合劑可列舉者有例如聚乙稀 醇、聚乙制 '乙基纖維素、甲基纖維素、阿拉伯膠、西 黃蓍膠、明膠、蟲膠、經丙基纖維素、經丙基澱粉、聚乙 烯吡咯啶酮等。 明膠粉末、結晶纖 葡聚糖、果膠等。 、聚乙二醇、二氧 崩散劑可列舉者有例如澱粉、洋菜、 維素、碳酸鈣、碳酸氫鈉、檸檬酸鈣、 潤滑劑可列舉者有例如硬脂酸鈉、滑石 106868-971127.doi 化矽、硬化植物油等。著色劑可使用容許添加於醫藥品 者。矯味矯臭劑可使用可可粉、薄荷腦、芳香酸、薄荷 ’由、龍腦、桂皮粉等。該等的錠劑可在顆粒劑上可具有糖 衣、明膠衣或依據其他需要之包衣。 調製注射劑或眼藥時,可依需要添加pH調整劑、緩衝 劑、安定化劑、保存劑等,依常法而製成皮下、肌肉内、 静脈内注射劑。注射劑或眼藥亦可將溶液放入容器後藉由A capsule, a syrup, an elixir, an oily or water-soluble suspension, and the like. The excipient may, for example, be lactose, corn flour, white sugar, glucose, sorbitol, crystalline cellulose or the like. The binder may, for example, be polyethylene glycol, polyethylene ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, propyl cellulose, propyl starch, Polyvinylpyrrolidone and the like. Gelatin powder, crystalline cellulose dextran, pectin and the like. Examples of the polyethylene glycol and the dioxic disintegrator include, for example, starch, agar, vitamins, calcium carbonate, sodium hydrogencarbonate, calcium citrate, and lubricants such as sodium stearate and talc 106868-971127. .doi phlegm, hardened vegetable oil, etc. The coloring agent can be used in a case where it is allowed to be added to a pharmaceutical product. As the flavoring agent, cocoa powder, menthol, aromatic acid, mint, borneol, cinnabar powder, and the like can be used. Such tablets may have a coating on the granules, a gelatin coat or a coating according to other needs. When preparing an injection or an eye drop, a pH adjuster, a buffer, a stabilizer, a preservative, etc. may be added as needed, and a subcutaneous, intramuscular, or intravenous injection may be prepared according to a usual method. Injections or eye drops can also be used after the solution is placed in a container.
冷凍乾燥等製成固形製劑,亦可製為使用時調製之製劑。 此外,可將一次投與量放入容器中,亦可將多次投與量放 入同一容器t。 本發明二水合物的投與量於用在人類時,成人每日通常 為0.01〜1000毫克,較佳為(UMOO毫克的範圍内,也可將 日置以一曰一次投與或分成2〜4次投與。 [實施例]The solid preparation can be prepared by freeze-drying or the like, and can also be prepared as a preparation prepared at the time of use. Further, one dose can be placed in the container, or multiple doses can be placed in the same container t. The dosage of the dihydrate of the present invention is usually 0.01 to 1000 mg per day for adults, preferably (in the range of UMOO mg, or may be administered once or divided into 2 to 4 times. Sub-investment. [Examples]
以下列舉實施例及試驗例以具體説明本發明,但是,並 非將本發明限定於該等者。 實施例1 將依國際㈣第99/2()62()號手冊上記載之方法所得之2 〇 克(S)-(-)-l-(4-氟基異喹啉_5_基)磺醯基_2_甲基_ι,4·升哌 畊鹽酸鹽(1)在80°C的加溫下溶解於水(3毫升)^接著,一 面加溫一面添加異丙醇(12毫升),確認為均勻後,放置於 室溫-夜使之結晶化。慮取析出之結晶後,在室溫乾燥Μ 小時,可製得⑺克⑽戲脚㈠]#氣基異嗤琳_5基) 磺醯基-2-甲基-1,4-升哌畊鹽酸鹽•二水合物。 土 106868-971127.doc •12· 1354670 元素分析値:C15H18N302FS · HC卜 2H20 理論値:C 45.51% ; Η 5.86% ; N 10.61% ; Cl 8.96% 實測値:C 45.50% ; Η 5.84% ; N 10.57% ; Cl 8.93% 藉由紅外線分光光度計所得之紅外線吸收光譜(Thermo Nicolet社製、AVATAR370 ; ATR法)於 854、974、1146、 1323及3418公分」附近有二水合物特有的吸收峯(圖1下 段)。表1顯示詳細的吸收位置及強度。另外,一併顯示無 水結晶的吸收峯(圖1上段、表2)。 [表1] 二水合物的紅外線吸收(位置:公分“、強度:°/〇R) 位匮 764.51 麵 80.630 位置 779.76 酿 91.146 位麼 794.63 強度 91.621 位置 854.41 強度 90.857 位廣 882.98 強度 91.724 位置 894.42 強度 89.039 位置 974. 74 強度 86.245 位置 1020. 91 強度 93.720 位置 1043. 96 強度 90.273 位置 1074.70 90,454 位置 1092.36 強度 94.291 位S 1130.49 強度 86.130 位置 1146.17 強度 81.445 位置 1178.81 強度 91.941 位匮 1272. 85 強度 89.759 位置 1323.30 強度 75.088 位傾 1350.82 強度 91.048 位置 1377. 13 強度 93.358 位置 1418.51 強度 94.514 位置 1448,58 強度 94.730 位置 1479.05 強度 94.217 位® H94.35 強度 93.546 位懂 1588.71 強庳 93.721 位置 2774.45 強度 94.646 位置 2 抑 4.37 強度 95.357 位懂 3418.71 強度 93.908 106868-971127.doc -13- 1354670 [表2] 無水結晶的紅外線吸收(位置:公分“、強度:%r) 位S 679- 34 強度 99. 252 位置 762. 59 強度 92.637 位置 773.67 強度 97.136 位置 790.25 強瑋 97.978 位置 807. 65 強度 99.013 位置 840.68 肆度 98.725 . 位置 871.31 強度 97.249 位置 m· 03 強度 96.797 位置 93.9. 89 強度_ 98.506 位置 954.86 強度 97.913 位置 992.25 強度 93.757 位S 1044.93 強度· 99.087 位置 1061.07 強度 98. 394 位置 1073.37 強度 99.155 位g 1098.17 強度 99.056 位置 1112.48 強度 97.383 位置 1129.22 強度 96.590 位置 1151.65 強度 93.492 位m 1205.14 強虔 96,423 位置 1221.03 触 97.745 位置 1273:55 強度 95.943 位鹿 1301.49 強度 97.9L7 位置 13U.42 強度 97.117 位置 1329,07 92.494 位置 1354, 18 ' 触 97.487 位辑 13S1.27 強度 91752 位置 1414.12 m 99,324 位置 1455.71 強度 97.838 位醪 1497.05 強度 99.039 位置 1586.02 強度 97.437 位置 1623. 73 強度 99,643 位置 2534.92 ' 強度 98.913 位置 2648. 09 強度 98.692 位置 2797. 7S 強度 99.062 位茵 2945'. 1Q 強度 99.554 以下亦同) 15.240、 30.060 、 粉末X光繞射(理學電機工業社製;Miniflex ; 顯示圖2的圖形,如表3所示,其在8.660、 17.180 、25.100 、25·780 、26.780 、28.100 、 106868-971127.doc -14- 1354670 3 3.200°有二水合物特有的繞射角度(20)。一併於表3顯示X 光繞射峯之1/2強度中繞射線的寬度(半高寬)、結晶面間隔(d 值)、繞射X光強度(強度)及繞射X光相對強度(相對強度)。 另外,無水結晶的粉末X光繞射圖示於圖3,繞射角度、 半高寬、d值、強度及相對強度表示於表4。 [表3] 二水合獅繞射角度The invention is specifically illustrated by the following examples and test examples, but the invention is not limited thereto. Example 1 2 gram of (S)-(-)-l-(4-fluoroisoquinoline-5-yl) obtained according to the method described in International Handbook No. 99/2() 62() Sulfosyl 2_methyl_ι, 4 liters of piperine hydrochloride (1) was dissolved in water (3 ml) under heating at 80 ° C. Then, isopropanol was added while heating. ML), after confirming to be uniform, it was allowed to stand at room temperature-night to crystallize. After taking out the precipitated crystals, drying at room temperature for Μ hours, can produce (7) grams (10) of the foot (a)] #气基异嗤琳_5 base) sulfonyl-2-methyl-1,4-litre Hydrochloride • Dihydrate. Soil 106868-971127.doc •12· 1354670 Elemental analysis 値: C15H18N302FS · HC Bu 2H20 Theory 値: C 45.51% ; 5.8 5.86% ; N 10.61% ; Cl 8.96% 値 C : C 45.50% ; Η 5.84% ; N 10.57 % ; Cl 8.93% The infrared absorption spectrum obtained by an infrared spectrophotometer (manufactured by Thermo Nicolet, AVATAR370; ATR method) has a dihydrate-specific absorption peak near 854, 974, 1146, 1323, and 3418 cm (Fig. 1 next paragraph). Table 1 shows the detailed absorption position and strength. In addition, the absorption peak of the anhydrous crystals is shown together (Fig. 1, upper part, Table 2). [Table 1] Infrared absorption of dihydrate (position: cm", strength: ° / 〇R) at 匮764.51 face 80.630 position 779.76 stuffed 91.146 bit 794.63 strength 91.621 position 854.41 strength 90.857 bit wide 882.98 strength 91.724 position 894.42 strength 89.039 Position 974. 74 Strength 86.245 Position 1020. 91 Strength 93.720 Position 1043. 96 Strength 90.273 Position 1074.90 90,454 Position 1092.36 Strength 94.291 Position S 1130.49 Strength 86.130 Position 1146.17 Strength 81.445 Position 1168.81 Strength 91.941 Bit 匮 1272. 85 Strength 89.759 Position 1323.30 Strength 75.088 bit Tilt 1358.82 Strength 91.048 Position 1377. 13 Strength 93.358 Position 1418.51 Strength 94.514 Position 1448,58 Strength 94.730 Position 1475.05 Strength 94.217 Positions H94.35 Strength 93.546 Positions 1568.71 Forced 93.721 Positions 2774.45 Strength 94.646 Position 2 Restricted 4.37 Strength 95.357 Positions 3418.71 Intensity 93.908 106868-971127.doc -13- 1354670 [Table 2] Infrared absorption of anhydrous crystals (position: cm", strength: %r) Position S 679- 34 Strength 99. 252 Position 762. 59 Strength 92 .637 Position 773.67 Strength 97.136 Position 790.25 Strong 97.978 Position 807. 65 Strength 99.013 Position 840.68 98 98.725 . Position 871.31 Strength 97.249 Position m· 03 Strength 96.797 Position 93.9. 89 Strength _ 98.506 Position 954.86 Strength 97.913 Position 992.25 Strength 93.757 Bit S 1044.93 Strength · 99.087 Position 1061.07 Strength 98. 394 Position 1073.37 Strength 99.155 Bit g 1098.17 Strength 99.056 Position 1112.48 Strength 97.383 Position 1129.22 Strength 96.590 Position 1151.65 Strength 93.492 bit m 1205.14 Strong 96,423 Position 1221.03 Touch 97.745 Position 1273:55 Strength 95.943 Deer 1301.49 Intensity 97.9L7 Position 13U.42 Strength 97.117 Position 1329,07 92.494 Position 1354, 18 ' Touch 97.487 Position 13S1.27 Strength 91752 Position 1414.12 m 99,324 Position 1455.71 Strength 97.838 Position 醪1497.05 Strength 99.039 Position 1568.02 Strength 97.437 Position 1623. 73 Strength 99,643 Position 2534.92 'Strength 98.913 Position 2648. 09 Strength 98.692 Position 2797. 7S Strength 99.062 Position 2945'. 1Q Strength 99.554 The same applies) 15.2 40, 30.060, powder X-ray diffraction (manufactured by Rigaku Electric Co., Ltd.; Miniflex; shows the graph of Figure 2, as shown in Table 3, which is at 8.660, 17.180, 25.100, 25·780, 26.780, 28.100, 106868-971127. Doc -14- 1354670 3 3.200° has a diffraction angle unique to dihydrate (20). Table 3 shows the width (half height and width) of the ray in the 1/2 intensity of the X-ray diffraction peak, the crystal plane spacing (d value), the diffracted X-ray intensity (intensity), and the relative intensity of the diffracted X-ray. (Relative Strength). Further, the powder X-ray diffraction of the anhydrous crystal is shown in Fig. 3. The diffraction angle, the full width at half maximum, the d value, the strength, and the relative intensity are shown in Table 4. [Table 3] Dihydrate lion diffraction angle
緹號 2Θ 半高寬 d値 強度 相對 搬 峯 緝號 20 半高寬 d値 sm 栢對 酿 1 3.420 0.141 25.8122 571 26 31 29.840 0.141 2.9916 1079 48 2 3. TOO 0.118 23. 8595 1002 45 32 30. ΟβΟ 0.188 2.9702 1157 52 3 3. 900 0.165 22.6364 931 44 33 30. 700 0J88 2.9098 745 33 4 4.140 0.212 21.3246 878 39 34 30. 980 0.141 2.8841 628 28 5 8.060 0.118 10.9600 360 16 35 32.160 0.165 2.7809 732 15 6 8. 660 0.165 10.2019 2151 96 36 32. 800 0.118 2. 7281 575 26 7 12.780 0.118 L 9208 469 21 37 33. 200 0.282 2. 6961 1339 60 » 13.240 0.165 0.6814 487 22 38 34.260 0.118 2.6151 577 26 9 13. 540 0.165 6.5340 543 25 39 35.840 0.188 2.5034 738 33 10 15.020 0.188 5.8933 1.269 57 40 3S. 100 0.165 2.4859 669 30 11 15,240 0.165 5.8088 1955 87 41 36.620 0.118 2.4518 739 33 12 15.460 0.141 5.7266 1759 78 42 37.700 0.235 2.4275 806 36 13 17. 180 0.188 5.1569 1184 53 43 38.320 0.212 2.3469 823 37 14 19.560 0.212 1 5345 520 24 44 38.900 0.165 2.3122 750 34 15 20.040 0.235 4.4270 596 27 45 39.340 0.118 2. 2S83 605 27 16 21.180 0:188 4.1912 916 41 46 39.480 0.212 2. 2805 528 28. 17 21. 540 0.165 4.Ϊ219 674 30 47 39.580. 0.118 2.2750 595 27 18 21, 980 0,188 4.0404 1757 78 48 40.900 0.306 2,2046 674 30 19 22. 380 0.188 3.9691 1100 49 49 42. 260 0.118 2.1367 637 29 20 23. 000 0.212 3. 8635 653 29 50 44.160 0.235 2.0491 610 27 21 24. m 0.118 3.5785 714 32 51 46·· 240 0.212 1.9646 614 28 22 25. 100 0.21.2 3.5448 1471 66 52 46.460 0.118 1.9529 563 25 23 25. 460 0.165 3.4955 1031 46 53 46.940 0.235 1.9340 627 28 24 25, 780 0.165 3.4528 2258 100 25 26* 780 0.165 3, 3261 1425 64 26 27. 060 0.188 3.2923 875 39 27 27. 600 0.165 3. 2291 1112 50 28 28.100 α.212 3.1728 1219 54 29 29.000 0.141 3.0763 610 27 30 29.100 0.1:1.8 3.0660 570 26 •15- 106868-971127.doc 1354670 [表4]缇号2Θ Half-height width d値 intensity relative to moving peak nickname 20 Half-height width d値sm cypress pair 1 3.420 0.141 25.8122 571 26 31 29.840 0.141 2.9916 1079 48 2 3. TOO 0.118 23. 8595 1002 45 32 30. ΟβΟ 0.188 2.9702 1157 52 3 3. 900 0.165 22.6364 931 44 33 30. 700 0J88 2.9098 745 33 4 4.140 0.212 21.3246 878 39 34 30. 980 0.141 2.8841 628 28 5 8.060 0.118 10.9600 360 16 35 32.160 0.165 2.7809 732 15 6 8. 660 0.165 10.2019 2151 96 36 32. 800 0.118 2. 7281 575 26 7 12.780 0.118 L 9208 469 21 37 33. 200 0.282 2. 6961 1339 60 » 13.240 0.165 0.6814 487 22 38 34.260 0.118 2.6151 577 26 9 13. 540 0.165 6.5340 543 25 39 35.840 0.188 2.5034 738 33 10 15.020 0.188 5.8933 1.269 57 40 3S. 100 0.165 2.4859 669 30 11 15,240 0.165 5.8088 1955 87 41 36.620 0.118 2.4518 739 33 12 15.460 0.141 5.7266 1759 78 42 37.700 0.235 2.4275 806 36 13 17. 180 0.188 5.1569 1184 53 43 38.320 0.212 2.3469 823 37 14 19.560 0.212 1 5345 520 24 44 38.900 0.165 2.3122 750 34 15 20.040 0.235 4.4270 596 27 45 39.340 0.118 2. 2S83 605 27 16 21.180 0:188 4.1912 916 41 46 39.480 0.212 2. 2805 528 28. 17 21. 540 0.165 4.Ϊ219 674 30 47 39.580. 0.118 2.2750 595 27 18 21, 980 0,188 4.0404 1757 78 48 40.900 0.306 2,2046 674 30 19 22.380 0.188 3.9691 1100 49 49 42. 260 0.118 2.1367 637 29 20 23. 000 0.212 3. 8635 653 29 50 44.160 0.235 2.0491 610 27 21 24. m 0.118 3.5785 714 32 51 46·· 240 0.212 1.9646 614 28 22 25. 100 0.21.2 3.5448 1471 66 52 46.460 0.118 1.9529 563 25 23 25. 460 0.165 3.4955 1031 46 53 46.940 0.235 1.9340 627 28 24 25, 780 0.165 3.4528 2258 100 25 26* 780 0.165 3, 3261 1425 64 26 27. 060 0.188 3.2923 875 39 27 27. 600 0.165 3. 2291 1112 50 28 28.100 α.212 3.1728 1219 54 29 29.000 0.141 3.0763 610 27 30 29.100 0.1:1.8 3.0660 570 26 •15- 106868-971127. Doc 1354670 [Table 4]
無观晶的ΜΙί角度 峯 辊骁 2Θ 半高寬 d値 相對 m. 峯 辑筘 2Θ 半高寛 d値 m 相對 m. 1 3.520 0.165 25.0791 488 11 31 27.700 0.118 3.2177 704 15 2 3.800 0.118 23.2328 719 15 32 28.180 0.165 3.1640 569 13 3 4.120 0.259 21.4281 698 IS 33 28. 700 0.141 3.1078 892 19 4 8.700 0.212 10.1551 729 16 34 29. 000 0.118 3.0763 879 19 5 · 9.720 0.235 9.0916 389 9 35 29· 320 0.165 3. 0435 695 15 6 11.240 0.118 7. 8653 386 9 36 29. 880 0.188 2.9877 643 14 7 11.560 0.118 7. 6483 452 !0 37 30. 940 0.188 2. 8877 654 14 8 11.880 o.m 7.4430 973 21 U 31.-560 0.259 2.8324 677 15 9 12.040 0.141 7.3445 972 21 39 32. 480 0.235 2. 7542 837 18 10 12.780 0.212 S. 9208 Π40 25 40 32. 980 0.118 2.7136 595 13 11 13.140 0.141 6.7320 414 9 41 34. 800 0.141 2. 5758 590 13 12 13.340 0.118 6.6315 424 9 42 3β, 560 0.118 2. 4557 620 14 13 !4.4S0 Ο.ίδδ 6.1U9 1696 36 43 36. 980 0.165 2.4288 710 16 14 15.320 0.165 5,7786 812 18 44 38.520 0.259 2. 3351 623 14 15 J5.560 0.165 5.6900 712 >6 45 4L300 0. 353 2.1841 653 14 16 17.260 0.188 5.1332 569 13 46 45. 820 0. 235 1.9786 559 12 17 17.920 0:212 4.9456 1310 28 18 18.580 0.212 4-7461 1003 22 19 19.120 0.212 4.6378 712 16 ίϋ 20.400 0.188 4,3496 582 13 21 21.020 0.259 4. 2227 650 H 22 21.340 0.118 4.1601 561 12 23 21.840 0.2 &9 4.0660 1668 36 24 21.860 0.118 4.0623 1643 3S 25 22. 500 0.212 3.9482 607 13 26 25. 480 0.2Γ2 3.4928 4713 100 27 25.840 0.165 3.4449 957 21 28 26. 220 o.m 3.3959 768 17 29 26.620 0.18$ 3.3457 1125 24 30 27,160 0. 235 3:2804 1044 23 此外,熱分析(理學電機工業社製,XRD-DSC)的結果示於 圖4及5。 實施例2 除了使用乙醇代替異丙醇外,和實施例1相同,製造(S)-(-)-1-(4 -氣基異喧琳-5-基)續醯基-2-甲基-1,4 -升。底^1井鹽酸 鹽•二水合物(2)。 -16- 106868-971127.doc 實施例3 將50.0克(S )-(-)-1-(4-說基異啥《#-5-基)續酿基·2·甲基· 1,4-升哌畊鹽酸鹽(1)在80°C的加溫下溶解於水(75毫升)。 接著’一面加溫一面添加丙嗣(300毫升),確認為均勻後, 放置於室溫一夜使之結晶化。濾取析出之結晶後,在室溫观ί 角度 angle angle roll 骁 2 Θ half height 値 d 値 relative m. peak 筘 2 Θ half 寛 d値m relative m. 1 3.520 0.165 25.0791 488 11 31 27.700 0.118 3.2177 704 15 2 3.800 0.118 23.2328 719 15 32 28.180 0.165 3.1640 569 13 3 4.120 0.259 21.4281 698 IS 33 28. 700 0.141 3.1078 892 19 4 8.700 0.212 10.1551 729 16 34 29. 000 0.118 3.0763 879 19 5 · 9.720 0.235 9.0916 389 9 35 29· 320 0.165 3. 0435 695 15 6 11.240 0.118 7. 8653 386 9 36 29. 880 0.188 2.9877 643 14 7 11.560 0.118 7. 6483 452 !0 37 30. 940 0.188 2. 8877 654 14 8 11.880 om 7.4430 973 21 U 31.-560 0.259 2.8324 677 15 9 12.040 0.141 7.3445 972 21 39 32. 480 0.235 2. 7542 837 18 10 12.780 0.212 S. 9208 Π40 25 40 32. 980 0.118 2.7136 595 13 11 13.140 0.141 6.7320 414 9 41 34. 800 0.141 2. 5758 590 13 12 13.340 0.118 6.6315 424 9 42 3β, 560 0.118 2. 4557 620 14 13 !4.4S0 Ο.ίδδ 6.1U9 1696 36 43 36. 980 0.165 2.4288 710 16 14 15.320 0.165 5,7786 812 18 44 38.520 0.259 2. 3351 623 14 15 J5 .560 0.165 5.6900 7 12 >6 45 4L300 0. 353 2.1841 653 14 16 17.260 0.188 5.1332 569 13 46 45. 820 0. 235 1.9786 559 12 17 17.920 0:212 4.9456 1310 28 18 18.580 0.212 4-7461 1003 22 19 19.120 0.212 4.6378 712 16 ϋ 20.400 0.188 4,3496 582 13 21 21.020 0.259 4. 2227 650 H 22 21.340 0.118 4.1601 561 12 23 21.840 0.2 &9 4.0660 1668 36 24 21.860 0.118 4.0623 1643 3S 25 22. 500 0.212 3.9482 607 13 26 25. 480 0.2 Γ2 3.4928 4713 100 27 25.840 0.165 3.4449 957 21 28 26. 220 om 3.3959 768 17 29 26.620 0.18$ 3.3457 1125 24 30 27,160 0. 235 3:2804 1044 23 In addition, thermal analysis (XRD-DSC, manufactured by Rigaku Denki Kogyo Co., Ltd.) The results are shown in Figures 4 and 5. Example 2 (S)-(-)-1-(4-carboisoindol-5-yl)-indolyl-2-methyl was produced in the same manner as in Example 1 except that ethanol was used instead of isopropanol. -1,4 - liter. Hydrochloride salt · dihydrate (2). -16-106868-971127.doc Example 3 50.0 g of (S)-(-)-1-(4-sayylisoindole "#-5-yl" continuation base ·2·methyl·1,4 - liter of peptinic acid hydrochloride (1) was dissolved in water (75 ml) under heating at 80 °C. Then, propylene (300 ml) was added while heating, and after confirming that it was uniform, it was allowed to stand at room temperature overnight to be crystallized. After filtering out the precipitated crystals, at room temperature
乾燥24小時,可製得45.4克(82.5%)(3)-(-)_1_(4-氟基異啥 啭-5-基)續酿基-2-曱基-1,4-升η底喷鹽酸鹽•二水合物(2)。 mp 25 8〇C 元素分析値:C15H18N302FS · HC1 · 2H20 理論値:C 45·510/〇 ; H 5.86%;N 10.61%;C1 8.96% 實測値:C 45.49%;Η 5.82%;Ν 10.56%;C1 8.95% 試驗例1(熱安定性) 將實施例1所製得之1克本發明二水合物置於密封容器内 測量,於40、60、及80°C的恆溫器内,保溫7及14日,評 估熱安定性。結果示於表5。 [表5] 保存溫度 保存期間 殘存率(%) 40°C 7曰 100.0 14曰 99.6 60°C 7曰 99.6 14曰 99.8 80°C 7曰 99.8 14曰 99.8 由表5可知,本發明二水合物在4〇β〇、6〇〇c、8〇〇c各個 溫度條件下,即使保存2星期,亦顯示良好的熱安定性。 試驗例2(吸濕性) 106868-971127.doc 將實施例1所製得之本發明二水合物及(S)-(-)-1-(4-氟基 異喹啉-5-基)磺醯基-2-甲基-1,4-升哌畊鹽酸鹽無水結晶各 100毫克裝入測量瓶中,以開封狀態放置於保持於25°C、 33%及92%RH的容器内。接著,經時地測量測量瓶,經由 求出重量增加以評估吸濕性。結果示於圖6及7。 由圖6及7明顯可知,無水結晶隨著時間經過,水分含量 變化成0〜40%,吸濕安定性低。相對於此,本發明二水合 物水分含量未變化,顯示良好的吸濕安定性。另外,本發 明二水合物在同一條件下經過2星期後仍安定。 於實施例1〜3所製得之本發明二水合物的元素分析、水 分含量、粉末X光繞射及紅外線吸收光譜結果統整地示於 表6。 [表6] 有機溶劑 異丙醇 乙醇 丙嗣 元素分析(C、Η、N、C1) 記載於實施例1 和實施例1 一致 記載於實施例3 水分含量 9.05 9.13 8.94 粉末X光繞射 記載於實施例1 和實施例1 一致 和實施例1 一致 紅外線吸收光譜 記載於實施例1 和實施例1 一致 和實施例1 一致 從表6可看出除異丙醇以外的乙醇及丙酮作為有機溶劑 時,元素分析、水分含量、粉末X光繞射及紅外線吸收光 譜顯示出二水合物的物性値。 實施例4 (大規模之再現性) 和實施例3同樣地,更進一步製造二組本發明二水合物 以確認再現性。結果示於表7。 106868-971127.doc •18- 1354670 [表7] 組別_ 1(實施例3:j ~ 2 元素分析(C、Η、Ν、C1)~記載於實施例3~ϊπ實施例3-致 水分含量(%) 8.87 8 89 粉末X光繞射 和實施例1 一致和實施例1 一致 -θ夕卜線吸收·光譜_和實施例1 一致和實施例1 一致 組別1係表示實施例3After drying for 24 hours, 45.4 g (82.5%) of (3)-(-)_1_(4-fluoroisoindol-5-yl) continuation-based 2-mercapto-1,4-liter η bottom can be obtained. Spray hydrochloride•dihydrate (2). Mp 25 8〇C Elemental analysis 値: C15H18N302FS · HC1 · 2H20 Theory 値: C 45·510/〇; H 5.86%; N 10.61%; C1 8.96% 値: C 45.49%; Η 5.82%; Ν 10.56%; C1 8.95% Test Example 1 (Thermal stability) 1 g of the dihydrate of the present invention obtained in Example 1 was placed in a sealed container, and the thermostats were kept at 40, 60, and 80 ° C for 7 and 14 Day, assessing thermal stability. The results are shown in Table 5. [Table 5] Storage temperature Preservation rate during storage (%) 40 ° C 7 曰 100.0 14 曰 99.6 60 ° C 7 曰 99.6 14 曰 99.8 80 ° C 7 曰 99.8 14 曰 99.8 From Table 5, the present invention dihydrate Under the temperature conditions of 4 〇β〇, 6〇〇c, 8〇〇c, good thermal stability was exhibited even after storage for 2 weeks. Test Example 2 (hygroscopicity) 106868-971127.doc The dihydrate of the present invention obtained in Example 1 and (S)-(-)-1-(4-fluoroisoquinolin-5-yl) were prepared. 100 mg of each of anhydrous sulfonyl-2-methyl-1,4-liter piperidine hydrochloride crystals were placed in a measuring bottle and placed in a container maintained at 25 ° C, 33% and 92% RH in an unsealed state. . Next, the measuring bottle was measured over time, and the weight gain was evaluated to evaluate the hygroscopicity. The results are shown in Figures 6 and 7. As is apparent from Figs. 6 and 7, the anhydrous crystals change over time as the moisture content changes to 0 to 40%, and the moisture retention stability is low. On the other hand, the moisture content of the dihydrate of the present invention did not change, and showed good moisture absorption stability. Further, the dihydrate of the present invention was stabilized after 2 weeks under the same conditions. Elemental analysis, water content, powder X-ray diffraction, and infrared absorption spectrum of the dihydrate of the present invention obtained in Examples 1 to 3 are collectively shown in Table 6. [Table 6] Organic solvent isopropanol ethanol oxime elemental analysis (C, Η, N, C1) is described in Example 1 and Example 1 consistently described in Example 3 Moisture content 9.05 9.13 8.94 Powder X-ray diffraction is described in Example 1 and Example 1 Consistent and Example 1 Consistent infrared absorption spectrum is described in Example 1 and Example 1 in agreement with Example 1 From Table 6, it can be seen that ethanol and acetone other than isopropanol are used as an organic solvent. Elemental analysis, moisture content, powder X-ray diffraction, and infrared absorption spectrum showed the physical properties of the dihydrate. Example 4 (Reproducibility on a large scale) Two sets of the dihydrate of the present invention were further produced in the same manner as in Example 3 to confirm the reproducibility. The results are shown in Table 7. 106868-971127.doc •18- 1354670 [Table 7] Group _ 1 (Example 3: j ~ 2 elemental analysis (C, Η, Ν, C1) ~ described in Example 3 ~ ϊ π Example 3 - Moisture Content (%) 8.87 8 89 Powder X-ray diffraction and Example 1 Consistent and Example 1 Consistent - θ 线 line absorption · Spectrum _ and Example 1 Consistent and Example 1 Consistent Group 1 shows Example 3
從表7可明顯看到全部組別之元素分析、水分含量、粉 末X光繞射及紅外線吸收光譜均顯示出二水合物物性値, 即使是大量規模亦能製得再現性好的本發明二水合物。 【圖式簡單說明】 圖1表示(S)_㈠·丨-㈠-氟基異喹啉_5•基)磺醯基_2曱基_ 1,4-升哌畊鹽酸鹽(無水結晶)之紅外線吸收光譜(上段)及 (S) ( )-1-(4-氟基異喹啉_5_基)磺醯基_2曱基·丨,4-升哌畊鹽 酸鹽·二水合物之紅外線吸收光譜(下段)。 圖2表不(s)-(-)-i_(4·氟基異喹啉_5_基)磺醯基_2_曱基_ 1,4·升哌畊鹽酸鹽•二水合物之粉末χ光繞射圖。It can be clearly seen from Table 7 that the elemental analysis, the moisture content, the powder X-ray diffraction, and the infrared absorption spectrum of all the groups all show the dihydrate physical properties, and the reproducibility of the present invention can be obtained even on a large scale. Hydrate. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows (S)_(I)·丨-(a)-fluoroisoquinoline-5(5)sulfonyl-2-indenyl-1-1,4-litrepine hydrochloride (anhydrous crystal) Infrared absorption spectrum (upper stage) and (S) ( )-1-(4-fluoroisoquinoline-5-yl)sulfonyl 2 fluorenyl hydrazine, 4-liter piperine hydrochloride · dihydrate Infrared absorption spectrum of the object (lower section). Figure 2 shows (s)-(-)-i_(4·Fluoroisoquinoline-5-yl)sulfonyl-2-ylinyl-1 1,4 liters of piperidine hydrochloride•dihydrate Powder calender diffraction pattern.
和實施例3—致 8.90 和實施例1 一致 和實施例1 一致 圖3表不(s)-(-)-i_(4_氟基異喹啉巧_基)磺醯基·2·曱基· Μ-升娘崎鹽酸鹽(無水結晶)之粉末χ光繞射圖。 表示(S)-(-)-i-(4_ ι基異喹啉_5基)磺醯基曱基· 1 ’4升辰井鹽酸鹽•二水合物之熱分析圖。 圖5表示(SM_M_(4_氟基異啥啉基)磺醯基_2_甲基_ 】,心升哌畊鹽酸鹽(無水結晶)之熱分析圖。 圖6表示⑻-㈠小⑷氣基異喧琳-5.基)續g基甲基. 升娘输鹽(無水結晶)於饥、相對濕度挪之吸濕 行動的經時變化圖。 I06868-971127.doc -19- 1354670 t ηSame as Example 3 - 8.90 and Example 1 are identical and Example 1 is consistent. Figure 3 shows (s)-(-)-i_(4_fluoroisoquinolinyl)sulfonyl-2-indenyl · Powder-light diffraction pattern of Μ- Sheng Nisaki hydrochloride (anhydrous crystal). A thermal analysis diagram showing (S)-(-)-i-(4_ ι-isoisoquinolin-5-yl)sulfonylfluorenyl·1'4 liters of the well hydrochloride•dihydrate. Fig. 5 shows a thermal analysis diagram of (SM_M_(4_Fluoroisoindolyl)sulfonyl-2-methyl-], a rosette (anhydrous crystal). Figure 6 shows (8)-(a) small (4) Gas-based isoindole-5. base) Continued g-methyl group. The time-dependent change of the moisture absorption action of Shengni salt (anhydrous crystal) in hunger and relative humidity. I06868-971127.doc -19- 1354670 t η
圖7表不(S)-(-)-l-(4 -鼠基異喧淋-5 -基)續酿基-2-甲基-1,4-升哌畊鹽酸鹽•二水合物之吸濕行動的經時變化圖。 圖8表不一面將(S)-(-)-l-(4 -亂基異啥淋-5-基)續酿基-2_ 甲基-1,4-升哌畊鹽酸鹽•二水合物升温一面測定水分量變 化時之經時變化的粉末X光繞射圖及熱分析圖。 106868-971127.doc -20-Figure 7 shows (S)-(-)-l-(4 - murine isoindole-5-yl) continued-branched-2-methyl-1,4-litre piperidine hydrochloride•dihydrate A graph of the change over time of the moisture absorption action. Figure 8 shows one side of (S)-(-)-l-(4 - 乱基异啥淋-5-yl) continually based on 2-methyl-1,4-litre peptonic acid hydrochloride • dihydrate The powder X-ray diffraction pattern and the thermal analysis chart of the time-dependent change when the water content changes are measured while the temperature is raised. 106868-971127.doc -20-
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KR101149954B1 (en) * | 2005-08-30 | 2012-06-01 | 아사히 가세이 파마 가부시키가이샤 | Sulfonamide compound |
US8415372B2 (en) | 2007-02-27 | 2013-04-09 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
WO2008105442A1 (en) * | 2007-02-28 | 2008-09-04 | Asahi Kasei Pharma Corporation | Sulfonamide derivative |
US8232292B2 (en) | 2007-07-02 | 2012-07-31 | Asahi Kasei Pharma Corporation | Sulfonamide compound and crystal thereof |
UA102128C2 (en) * | 2008-12-05 | 2013-06-10 | Х. Луннбек А/С | Nalmefene hydrochloride dihydrate |
WO2012026529A1 (en) | 2010-08-26 | 2012-03-01 | 興和株式会社 | Novel production method for isoquinoline derivatives and salts thereof |
EP3626245B1 (en) * | 2013-04-24 | 2021-05-05 | Kyushu University, National University Corporation | Therapeutic agent for eyeground disease |
KR101846804B1 (en) * | 2014-09-25 | 2018-04-06 | 코와 가부시키가이샤 | Pharmaceutical preparation for an aqueous composition comprising ripasudil |
US10369781B2 (en) * | 2015-01-08 | 2019-08-06 | Hewlett-Packard Development Company, L.P. | Mobile printers |
CN107216311B (en) * | 2016-03-21 | 2019-09-03 | 山东诚创医药技术开发有限公司 | (s) -4- [(4- fluoro isoquinolin -5- base) sulfonyl] -3- methyl-1, the refining methd of 4- Diazesuberane hydrochloride |
CN106496189A (en) * | 2016-10-10 | 2017-03-15 | 江苏礼华生物技术有限公司 | Hydrochloric acid Ripasudil crystal formations |
CN107164328A (en) * | 2017-06-30 | 2017-09-15 | 太仓卡斯特姆新材料有限公司 | A kind of method for resuscitation of the breast cancer cells of high stability MCF 7 |
US11427546B2 (en) | 2018-12-17 | 2022-08-30 | D. Western Therapeutics Institute, Inc. | Form of isoquinoline sulfonamide |
US20230024516A1 (en) | 2019-06-21 | 2023-01-26 | Guangzhou Ocusun Ophthalmic Biotechnology Co., Ltd. | Isoquinolinone derivatives serving as rock protein kinase inhibitors and use thereof |
CN114644618A (en) | 2020-12-21 | 2022-06-21 | 广州润尔眼科生物科技有限公司 | Salt form of isoquinolinone compound as ROCK protein kinase inhibitor and preparation method thereof |
Family Cites Families (4)
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---|---|---|---|---|
JP3734531B2 (en) * | 1995-06-29 | 2006-01-11 | 旭化成ファーマ株式会社 | 1- (5-Isoquinolinesulfonyl) homopiperazine hydrochloride trihydrate |
WO1997002260A1 (en) * | 1995-07-03 | 1997-01-23 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
CN1210521A (en) * | 1996-02-02 | 1999-03-10 | 日本新药株式会社 | Isoquinoline derivatives and drugs |
AU9646198A (en) * | 1997-10-22 | 1999-05-10 | Nippon Shinyaku Co. Ltd. | Isoquinoline derivative and drug |
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